The safety database for Belimumab ( Benlysta ) is based primarily on the three randomized, placebo-controlled studies ( L02, C1056, and C1057 ) and their safety extensions.

Death

There were a total of 14 deaths across the placebo-controlled, double-blind treatment periods ( studies L02, C1056, and C1057 ), with 3 ( 0.4% ), 5 ( 0.7% ), and 6 ( 0.9% ) occurring in patients in the placebo, Belimumab 1 mg/kg, and Belimumab 10 mg/kg group, respectively. One additional death in a patient treated with Belimumab 1 mg/kg occurred 15 weeks after patient withdrawal. The death rate per 100 patient-years was 0.79 and 0.43 for Belimumab and placebo, respectively, with a rate ratio of 1.83. Even if the single patient in the Belimumab group who died 15 weeks post-study withdrawal was removed from the exposure-adjusted analysis, the death rate with Belimumab remains higher than for the placebo group ( i.e. 0.73 versus 0.43 ). of the 14 deaths that occurred in the placebo-controlled double-blind treatment periods, 2 occurred in study L02, 3 in study C1056, and 9 in study C1057. There were 4 deaths related to infection ( 1 in placebo group, 1 in Belimumab 1 mg/kg group, and 2 in Belimumab 10 mg/kg group ). In addition there were 2 deaths where infection may have contributed to the deaths ( 1 in Belimumab 1 mg/kg group, and 1 in Belimumab 10 mg/kg group ). There were 2 suicides, both in patients treated with Belimumab ( 1 in Belimumab 1 mg/kg group, and 1 in Belimumab 10 mg/kg group ). There was 1 cancer-related death in a patient treated with Belimumab 1 mg/kg. The largest number of deaths was from study C1057, which was conducted primarily in Latin America and Asia ( 88% patients were enrolled from these regions ).

Serious Adverse Events

Infection was the most frequent serious adverse event with 5.2%, 6.8%, and 5.2%, occurring in patients in the placebo, Belimumab 1 mg/kg, and Belimumab 10 mg/kg groups, respectively. Psychiatric and nervous system serious adverse events were numerically more common with Belimumab than with placebo. Depression was the most frequent serious adverse event under the psychiatric disorder system organ classification with 0.1% ( 1 patient ), 0.4% ( 3 patients ), and 0.4% ( 3 patients ), occurring in patients in the placebo, Belimumab 1 mg/kg, and Belimumab 10 mg/kg groups, respectively.

Infections

Infections associated with Belimumab treatment deserve special attention given that the mechanism of action of Belimumab is to inhibit BLyS, which directly affects B cell function. In the clinical program infections occurred more often with Belimumab treated patients compared to the placebo treated patients. The most frequent infections in the clinical program were upper respiratory tract infection ( URTI ), urinary tract infection ( UTI ), nasopharyngitis, sinusitis, and bronchitis. Of these, nasopharyngitis and bronchitis occurred more commonly with Belimumab treatment compared to placebo. There were 2 opportunistic infections, both in the Belimumab 10 mg/kg group. These included a disseminated CMV infection on day 62, and an Acinetobacter bacteremia on day 15. There were 4 infection related deaths with a numerical imbalance that favored placebo treatment over Belimumab treatment as discussed above. The causes of these deaths were sepsis ( placebo group ), cellulitis leading to sepsis ( Belimumab 1 mg/kg group ), cutaneous infection leading to sepsis ( Belimumab 10 mg/kg group ), and infectious diarrhea ( Belimumab 10 mg/kg group ).

Malignancy

Malignancies associated with Belimumab treatment deserve special attention given that Belimumab affects the immune function. There were 5 solid organ malignancies in the clinical program. These included a stomach carcinoid ( placebo group, day 202 ), a breast cancer ( Belimumab 1 mg/kg, day 102 ), a cervical cancer ( Belimumab 1 mg/kg, day 439 ), an ovarian cancer ( Belimumab 1 mg/kg, day 21, patient died ), and a thyroid cancer ( Belimumab 1 mg/kg, day 378 ). There were 4 non-melanoma skin cancers, 2 basal cell carcinomas, and 2 squamous cell carcinomas ( 1 in the placebo group, 3 in the Belimumab 1 mg/kg group ). There were no reported solid organ malignancies in the Belimumab 10 mg/kg group, and there were no reported hematological malignancies.

Suicides and psychiatric events

There were two completed suicides across the double-blind placebo controlled studies, both in patients treated with Belimumab ( one each in study L02 and study C1057 ). In addition there was another completed suicide in a Belimumab treated patient during the safety extension period of study L02 ( study L99 ). There were four cases of suicide attempts or suicidal ideation, all in patients treated with Belimumab ( one each in placebo-controlled studies L02 and C1057, and two in the safety extension period of study L02 called study L99 ). Psychiatric and nervous system adverse reactions classified as serious adverse events were numerically more common in patients treated with Belimumab than with placebo. Depression was the most frequent serious adverse event under the psychiatric disorder category with 0.1% ( 1 patient ), 0.4% ( 3 patients ), and 0.4% ( 3 patients ), occurring in patients in the placebo, Belimumab 1 mg/kg, and Belimumab 10 mg/kg groups, respectively. Psychiatric events not classified as serious adverse events, specifically depression/depressed mood, were more frequent in patients treated with Belimumab than with placebo. The frequencies of depression/depressed mood were 30 ( 4.4% ), 43 ( 6.4% ), 12 ( 10.8% ), and 36 ( 5.3% ) in placebo, Belimumab 1 mg/kg, Belimumab 4 mg/kg, and Belimumab 10 mg/kg groups, respectively. Although there is no known biological mechanisms for suicides and psychiatric events with Belimumab at this time, and patients with systemic lupus erythematosus ( SLE ) are known to have neuropsychiatric events and are at higher risk of suicide, nevertheless, there was a numerical imbalance that favored placebo over Belimumab in these double-blind placebo-controlled studies. The applicant has not formally assessed the safety database for treatment-emergent suicidality ( suicidal ideation and behavior, both nonfatal and fatal suicide attempts ) using commonly accepted methodologies, such as CCASA codes and definitions.

Immunogenicity, Anaphylaxis, and Infusion Reactions

The rate of immunogenicity with Belimumab was approximately 5% of patients in the randomized placebo-controlled studies. The frequency of hypersensitivity reactions ( including anaphylaxis ) and infusion reactions combined was reported as 17% and 15%, in Belimumab and placebo treatment arms, respectively. The reason for the observed high frequency in placebo treated patients is not clear. There were 3 cases of anaphylaxis in patients treated with Belimumab compared to none in patients treated with placebo, which results in a relatively low frequency of anaphylaxis of 0.2% with Belimumab. Further analysis of the entire safety database is necessary to determine the frequency of anaphylaxis and infusion reaction using accepted diagnostic criteria for anaphylaxis, accounting for patients who may have received incorrect treatment ( Belimumab instead of placebo ), and also addressing the impact of pre-treatment with antihistamine and corticosteroids, which were allowed at the discretion of the investigator.